Process for the preparation of 17alpha-alkynl-17beta-alkanoyloxy steroids of the androstane and estrane series



United States Patent Office 3,409,643 Patented Nov. 5, 1968 s y No Drawing. Filed Mar. 11, 1966, Ser. No. 533,435

Claims. (Cl. 260-397.5)

' ABSTRACT OF THE DISCLOSURE A novel process for the preparation of 17a-alkynyll7fl-alkanoyloxy steroids of the androstane and estrane series comprises subjecting a 17-keto steroid of the androstane and estrane series to the acetylide and adding in situ to the 17a-alkynyl-l7B-hydroxy metal salt intermediate thereby formed, an aeylating agent selected from the group consisting of a lower alkanoyl anhydride and a lower alkanoyl halide. V

This process advantageously performs concomitantly both an alkynation and esterification reaction and provides amethod for preparing an ester of a tertiary alcohol under mild conditions in a medium which will not effect functional groups or systems which are highly reactive or sensitive to vigorous conditions or strongly acidic and strongly basic media.

This process is of particular use in the conversion of 3- methoxy 2,5 (10) esteradien-l7-one to 3-methoxy-17aethinyl 2,5(10) esteradien-l7/3-ol l7-acetate, a known, valuable intermediate.

This invention relates to a novel process and to novel intermediates produced thereby.

the 17u-alkynyl-17fi-hydroxy steroid thereby formed, and thereof under the vigorous conditions (i.e. high temperatures and/or in strongly acidic mediums) necessary operation, thus advantageously eliminating the steps of preparing per se and isolating the 17a-alkynyl-l7/3-hydroxy steroid intermediate required in prior art methods.

Additionally, by my process, whereby an acylating agent (eg. a lower alkanoyl anhydride or a lower alkanoyl halide) is added in situ to a l7a-alkynyl-l7 3-hydroxy metal salt intermediate, it is now possible to prepare an ester of the tertiary alcohol at C-17 under mild conditions (i.e. at room temperatures, and in a medium which is, in effect, non-reactive, i.e. does not cause transformations usually effected by strongly acidic or strongly basic media). The process of this invention is thus a method of preparing esters at C-17 of l7a-alkynyl-l7fiand 3-ethoxy-A which are highly reactive or sensitive choire when I hydroxy steroids and particularly hydroxyl group. Thus, preparation of 3-methoxy-17a-ethinyl-2,5(10)-esteradien- 17,8-01 l7 -aeetate (an intermediate in the preparation of therapeutically valuable l9-n0r steroids) via methods known in the art involves reacting 3-methoxy-l7a-ethinyl- 2,5 10)-estradien-17B-ol withv acetic anhydride in pyridine at elevated temperatures or with acetyl chloride in pyridine. Both the aforementioned reaction mediums cause involving destruction of the existing A-ring sys em such as conversion of the 3-methoxy- A sysem to a 3-keto-l9-nor-A system or to an aromatic A-ring system (i.e. 3-methox-y-A so that only a small yield of the desired 3-methoxy-l7a-ethinyl- 2,5(10)-estradien-17,B-ol 17-acetate is formed. By my invention, however, 3-methoxy-l7a ethinyl-2,5(10)-estradien-17,B-ol l7-acetate is conveniently prepared via a one vessel process in good yields from 3-methoxy-2,5(10)- acetic anhydride. The 3-methoxy 171x ethinyl-2,5(l0)- estradien-l7B-ol 17-acetate thereby formed, upon reaction with mild acid, e.g. oxalic acid, is converted to 1711- ethinyl-5(10)-estren-17B-ol l7-acetate which when subjected to the action of oxygen according to procedures known in the art, yields lOfi-hydroperoxy-l7a-ethinyl-l9- nor-4-androsten-17B-ol l7-acetate, a compound demonstrating anti-fertility activity.

In general, when carrying out my process, an alkali metal acetylide, e.g., sodium acetylide, is added to a 17- keto steroid of the androstane and pregnane series, e.g., 5-androsten-3 8-ol 17-one and 3-methoxy-2,5(10)-estradien-17-0ne, in a non-interfering solvent, having a high dielectric constant 17a-ethinyl-5-pregnene-3fl,17B-diol 17-so- 3-methox -l7a-ethinyl-2,5 10) -estradien- 175-01 sodium salt, respectively, there is added, in situ,

alkynating agent. The resulting Not-ethinyl-l7 3-alkanoyloxy steroid, e.g., 17a-ethinyl-5-androstene-3 8,17,8-diol disuch as tetrahydroas solvents for my are alkali metal acetylides which term (as used throughout the instant specification and claims) includes lithium and sodium acetylide whereby, together with the in situ addition of an alkanoyl anhydride or halide, are prepared l7a-ethinyl-l71S-alkanoyloxy derivatives, as well as substituted alkali metal acetylides, and, in particular, alkylsubstituted and halogeno-substituted alkali metal acetylides, such as sodium methyl acetylide, lithium chloroacetylide, and lithium bromoacetylide, whereby, together with the in situ addition of an alkanoyl anhydride or halide, are prepared l7a-methylethinyl-, l7a-chloroethinyl-, and l7a-bromoethinyl-l7fl-alkanoyloxy derivatives, respectively.

Acylating agents contemplated for use in the process and halides of carboxylic carbon atoms including the anhydride and acid halides of lower alkanoic acids such as acetic acid, propionic acid, t-butyric acid, valeric acid, and of aryl carboxylic acids such as benzoic and toluic acids, and the like. When an alkanoic acid derivative having up to 4 carbon atoms is desired, an acid anhydride is the acylating agent of choice.

The concomitant alkynation and esterification is completed within a very short time, the alkynation usually being completed within approximately a half-hour when the solvent is a disubstituted alkanoic acid amide and within about three hours when tetrahydrofuran is used as solvent. After addition of the acylating agent to the alkynated reaction mixture in situ, only a short reaction time is usually required (and sometimes but a minute or two) prior to pouring the reaction mixture into Water and isolating the resulting product.

My process finds its greatest usefulness in the preparation of 17a-alkynyl-l7n-alkanoyloxy derivatives of steroids containing acid sensitive function, such as described hereinabove. In general, however, any l7-keto steroid of the androstane and estrane series may be subjected to th action of an alkyn-at-ing agent followed by the in situ addition of a lower alkanoic anhydride or halide and there will be formed a l7a-alkynyl-l7fl-lower alkanoyloxy steroid of the androstane and estrane series.

Included among the 17-keto estranes useful as starting compounds are 3 methoxy 2,5(10) estradien-l7-0ne, estrone, and methyl analogs of estrone such as 1,2-dimethylestrone, 2methylestrone, lfi-methylestrone, 6B- methylestrone; unsaturated analogs thereof such as 6- dehydroestrone, 1-methyl-6-dehydroestrone, 1,2-dimethyl- 6-dehydroestrone, 6-methyl-6-dehydroestrone, 7-dehydr0- estrone (equilin), 6,8-bis-dehydroestrone (equilenin); hydroxylated derivatives and ethers thereof such as 65- methyl 7a hydroxyestrone, llB-hydroxyestrone, l-methoxyestrone and Z-methoxyestrone.

Some 17-keto androstanes useful as starting compounds are S-androsten-Sfl-ol-l7-one, 4-androstene-3,ll,l7-trione, 16B-methyl-19-nor-4-androstene-3,17-dione, 4-androstene- 3,17-dione, 4-androsten-35-ol l7 one, l9-nor-4-androstene-3,l7-dione, 5-androsten-3u-ol-l7-one, 1,4,6-androstatriene-3,l1,17-trione, S-androstene-Mjfl diol-17-one, 6-fluoro (a and B)-4-androsten-l7-one, 19-nor-4-androstene-ll,l7-dione, 4 androstene 11,17 dione, llB-hydroxyandrostan-l7-one, 1,4-androst-adiene-3,l7-dione.

When it is desired that an ether derivative be present in a l7u-a1kynyl-17fi-lower alkanoyloxy androstane or estrane prepared by my process, the hydroxyl functions in the l7-keto starting steroid, e.g. as in estrone (3-hydroxy- 1,3,5(l0)-estratrien-17-one) are preferably converted to their ether derivatives (e.g. estrone methyl ether) prior to reaction with sodium acetylide in dimethylformamide followed by acetic anhydride (for example) to obtain the corresponding 17a-alkynyl-17B-lower alkanoyloxy derivative thereof, e.g. 17 a-ethinylestradiol 3-methyl ether 17 acetate.

When preparing l7a-alkynyl-17B-1ower alkanoyloxy estranes and androstanes having free hydroxyl functions, the hydroxylated 17-keto starting steroids of the estrane and androstane series are conveniently converted to their tetrahydropyranyl ether derivatives prior to concomitant alkynation and esterification at Cl7. Treatment of the tetrahydropyranyl ether derivatives of the 17a-alkynyll7fi-alka'noyloxy compounds thereby formed with dilute acid removes the tetrahydropyranyl ether function with ease to yield the free hydroxy analogs. Thus, for example, estrene and 5-an'drosten-3p-ol-l7-one, upon reaction with dihydropyran in the presence of a strong acid such as ptoluenesulfonic acid (according to known procedures) will give the corresponding tetrahydropyranyl ether derivatives, e.g. estrone B-tetrahyd-ropyranyl ether and S-androsten-3fl-ol-l7-one 3-tetrahydropyranyl ether. Reaction of each of the foregoing with sodium acetylide in dimethylformamide followed by the in situ addition of acetic anhydride will yield l7u-ethinylestradiol 3-tetra-l1ydro pyranyl ether l7-acetate and l7a-ethinyl-Sandrostene-3B, l7fl-diol I i-tetrahydropyranyl ether l7-acetate, respectively. After the isolation of these derivatives (i.e. after the addition of water to the reaction medium and filtration or extraction thereof) the addition of acetic acid or hydrochloric acid to the derivative in aqueous alcohol will remove the tetrahydropyranyl group and there is obtained the free hydroxylated derivative, e.g. l7 a-ethinyl estradiol l7-acetate and 5-androstene-3;9,l7fl-diol l7-acetate, respectively.

Hydroxyl functions in the 17-keto-androstane and 17- keto-estrane starting steroids which are not protected prior to alkynation and esterification at C-l7, are transformed to their lower alkanoate ester derivatives under the conditions of my process. Thus, treatment of estrone and 5- androsten-35-ol-17-one with sodium acetylide in dimethylformamide followed by acetic anhydride, and isolation of the thereby formed l7u-ethinyl-l75-acetoxy derivatives by the addition of water followed by extraction and recrystallization will yield l7a-ethinyl estradiol diacetate and 17aethinyl-5-androstene-3{3,l7fl-diol diacetate, respectively. When preparing 17a-alkynyl-17fl-alkanoyloxy estranes and androstanes containing other esterified hydroxyl groups, the quantity of alkanoic acid anhydride which is to be added in situ should be increased by about one mole for each free hydroxyl group to ensure complete esterification of the resulting product. The esters of primary and secondary alcohols in the l7a-alkynyl-17B-acyloxy derivatives thus prepared may be converted to the corresponding free hydroxyl functions by preferential hydrolysis according to procedures known in the art. Thus l7a-ethinylestradiol diacetate and 17a-ethinyl-5androstene-35,175- diol diacetate upon treatment with a half-molar quantity of sodium carbonate in aqueous methanol yields 17aethinylestradiol 17-ac'etate and 17a-ethinyl-5-androstene- 35,17fl-diol 17-acetate, respectively.

When the hydroxyl functions in the starting 17-ketoandrostane or l7-keto estrane are hindered secondary or tertiary and, in carrying out my process, there is employed .a molar quantity of acylating agent approximately equivalent to that of alkylating agent, there is obtained a 1711- alkynyl-l7fl-acyloxy-androstane or estrane possessing unesterified secondary or tertiary hydroxyl functions. Thus, androstan-llB-ol-l7-one, upon reaction with about three moles of sodium acetylide followed by treatment with about three moles of acetic anhydride will yield ethinylandrostane-l15,17B-diol 17 -acetate.

Starting compounds possessing a A -3-keto moiety, e.g. l9-nor-4-androstene-3,l7-dione and 6a-fluoro-4-androsten- 3,17-dione, are preferably converted to the corresponding alkyl enol-ether derivative prior to alkynation and esterification in order to obtain the coresponding l7a-alkynyl- 17fl-lower alkanoyloxy-4-androsten-3-one. Thus, 19-nor-4- androstene 3,17 dione 311(1600 fluoro 4 androsten 3, l7-dione, upon treatment with ethyl orthoformate in dioxane in the presence of acid, accordng to known procedures, are each converted to the corresponding ethyl enol-ether intermediate, i.e. 3-ethoxy-l9-nor-3,S-androstadien-l7-one and 3-ethoxy-6-fiuoro-3,5-androstadien-l7- one, respectively, which, upon reaction with sodium.

acetylide in dimethylformamide followed by the in situ addition of acetic anhydride, yields 3-ethoxy-17a-ethinyl- 19-nor-3,5-androstadien-l7 3-01 17-acetate and 3-ethoxy-6- fluoro-3,5-androstadien-17,8-01 17-acetate, respectively. Treatment of the foregoing with dilute hydrochloric acid in aqueous methanol regenerates the 3-keto-A -system and there is formed 17a-ethinyl-19-nor-4-androsten-1718-01-3- one l7-acetate (17u-ethinyl-19-nor-testosterone 17-acetatethe known progestational agent, N orlutate) and 6afiuoro-l7a-ethinyl-4-androsten-17 -ol-3-one 17-acetate.

In order to prepare 17u-alkynyl-17 3-lower alkanoyloxy androstanes having a 3-keto-A system from the corresponding 3,17-diketo-A androstane by my process, it is one l7-acetate.

In general, Without effecting the course of my process (i.e. the concomitant formation of a 17a-alkynyl-l7/3- alkanoyloxy steroid from a 17-keto precursor), the starting l7-keto-androstanes and l7-keto-estranes may have double bonds present in the steroidal nucleus such as at C1 and C-4 (subject to special treatment as described hereinabove), at C-6, C-7, C-8, C9(1l) and C-ll; methyl and hydroxy substituents and derivatives thereof (e.g. esters and ethers) such as at C-4, C6, C-7, and

-11; fluoro, as at C6; and keto groups such as at C-3 (in a A*- and A A-ring) and at C-ll. Unprotected keto groups present other than at C-3 and/ or C-ll will undergo competing alkynation reactions to form the corresponding alkynated derivatives. Thus, androsane-3,l7-dione acetylide in dimethylformaddition of acetic anhydride Will yield 3,17-bis-ethinyl-androstame-3,l7,B-diol diacetate.

When preparing a 9a-halogeno-1lfi-hydroxy-Ih-ah kynyl-l7,8-alkanoyloxy-androstane or estrane, the substituents at C-17 are preferably introduced prior to those at C-9 and Cl1. Thus, 4,9(11)-androstadiene-3,17-dione after conversion to the corresponding 3-ethyl-enol-ether followed by treatment of the 3-ethoxy-3,5,9(l1)-androstatrien-17-one thereby formed dimethylformamide and the in situ addition of acetic anhydride, yields 3-ethoxy-17a-ethinyl-3,5,9(l1)-androstatrien-l7/8-ol 17-acetate convertible by treatment with acid to l7a-ethinyl-4,9( l 1)-androstadien-17 3-ol 17-acetate.

Treatment of the foregoing with hypobromous acid acvious equivalents will be apparent and the invention is to be limited claims.

Example 1.3 methoxy-17a-ethinyl-2,5( l0)-estradien- 17 3-01 l7-acetate (A) To a solution of 40 g. of 3-methoxy-2,5(l0)- estradien-l7-one in 800 ml. of dimethylforma-mide under alkanoate ester, i.e. 3-methoxy-17a-ethinyl-2,5(lO)-estradien-l7fi-ol 17-propionate and 3-methoxy-17a-ethiny1- 2,5 10)-estradien-l7fl-ol l7-n-butyrate, respectively.

(B) To a solution of 0.5 g. of 3-methoxy-2,5 10)-estradien-17-one in 5 ml. of tetrahydrofuran, add 5 ml. of a mixture comprising 18 percent sodium acetylide in xylene. Stir under nitrogen at 25 C. for four hours. Add 1.6 ml. of acetic mixture into ice water, the xylene. Collect by filtration the resulting precipitate comprising 3-methoxy- 17a-ethiny]-2,5(10)-estradien-l7fi-ol 17-acetate by filtration. Purify by crystallization from methanol containing a drop of pyridine.

(C) In a manner similar to that described in procedure 1A, treat 3-ethoxy-2,5(10)-estradien-17-one with sodium by acetic anhydride. Isolate and purify product in the described manner-to give 3- ethoxy-l7u-ethinyl-2,5(10)-estradien-17,8-01 17-acetate.

Example 2.17a-ethinyI-4-estren-17,3-01-3-0ne 17-acetate 17a-ethinyl-19-nor-testosterone 17ace'tate) (A) Dissolve l g. of 3-methoxy-17a-ethinyl-2,5(10)- estradien-l7fi-ol 17-acetate in 180 ml. of methanol and 20 ml. of water. chloric acid, heat into Water and collect by filtration the resulting precipitate comprising l7a-ethinyl-4-estren-17B-ol-3-one 17-acetate. In a similar manner, treat each of 3-methoxy-176rethinyl-2,5(10)-estradien-l7fl-ol l7-propi0nate and 3- methoxy-17a-ethinyl-2,5(l0) estradien-17fi-ol 17-n-butyrate With hydrochloric acid in methanol. Isolate the remanner described above to obtain, respectively, l7a-ethinyl-4-estren- 1 7/3-01-3 -one l7-propionate and 17a-ethinyl-4-estren-3-one 17-n-butyrate.

Alternatively, the compound of this example may be prepared as described below in procedures 2B and 2C.

(B) ethinyl 5(10) estren 17,6 ol 3 one 17-acetate.Suspend 19 g. of 3-methoxy-l7a-ethinyl-2, 5(l0)-estradiene-l7/3-0l 17-acetate in 1634 ml. of mething precipitate comprising 17a-ethinyl-5(l0)-estren-l7B- ol-3-one 17-acetate.

(C) l7u-ethinyl-4-estrenl 7 9-ol-3-one To a solution of l g. of 17a-ethinyl-5(l0)-estren-l7/3- ol-3-one l7-acetate in ml. of methanolinto water and collect by filtration the resulting precipitate comprising 17a-ethinyl-4-estren-l7,3-ol-3-one 17-acetate. I

In a similar manner to that described in procedures B and C above, treat each of 3-methoxy-l7a-ethinyl-2,5- (l0)-estradien-l7/3-ol l7-propionate and 3-methoxy-l7aethinyl-2,5(10)-estradien-17 9-ol 17-n-butyrate in methanol with oxalic acid, and isolate the resultant respective products comprising l7a-ethinyl-5(10)-estren-175-ol-3- one 17-propionate and 17a-ethinyl-5(10)-estren-175-ol-3- one' l7-n-butyrate. Treatment of each of the foregoing esters with methanolic hydrochloric acid according to Procedure 2C yields respectively 17a-ethinyl-4-estren-175- ol-3-one 17-propionate and l7a-ethinyl-4-estren-175-01-3- o'ne '17-n-butyrate.

Example 3.-lO-hydroperoxy-17u-ethinyl-4-estren-l75- ol-3-one 17-acetate Dissolve 13 g. of 17a-ethinyl-5(10)-estren-175-ol-3-one l-7-acetate (the compound of Example 2B) in 200 ml. of carbon tetrachloride. Pass oxygen through the solution while illuminating the solution with four fluorescent lights (four watts each). A precipitate slowly forms. Collect the resultant precipitate after 20,30 and 95 hours. Chromatograph the combined precipitate over 400 g. of silica gel eluting with increasing percentages of ethyl acetate in chloroform. Combine the like fractions thin layer chromatography and by infrared and ultraviolet spectra data. Evaporate the combined fraction in vacuo to a residue comprising l-hydroperoxy-l7tat-ethinyl-4-estren-175-ol-3-one l7-acetate. Purify by crystallization from aqueous methanol. M.P. 178-180 C. [ab-29 (dioxane).

Similarly, in the above procedure by substituting 17aethinyl-S(10)-estren-175-ol-3-one 17-acetate the corresponding l7-propionate and n-butyrate ester thereof, there is obtained lO-hydroperoxy-l7a-ethinyl-4-estren-175-ol- 3-one l7-propionate and lO-hydroperoxy-l7a-ethinyl-4- vestren-175-ol-3-one 17-n-butyrate, respectively.

0 Example 4.10-hydroperoxy-17a-ethinyl-4-estrene-35,

175-diol 17-acetate and the 3a-epimer thereof To a solution of 50 mg. of 10-hydroperoxy-17 tx-ethinyl- 4-estren-175-ol-3-one l7-acetate in 105 ml. of methanol at room temperature, add 10 mg. of sodium borohydride in 10 ml. of methanol. Stir at room temperature for 90 minutes, then cautiously add glacial acetic acid dropwise until the reaction mixture is about pH 7. Concentrate the reaction mixture in vacuo to a residue comprising 10- ;hydroperoxy 17a ethinyl 4 estrene 35,175 diol 17-acetate and the 3a-hydroperoxy epimer thereof.

Purify by dissolving the residue in ethyl acetate, washing the organic layer successively with dilute sodium bicarbonate, then water. Evaporate the ethyl acetate solution to a residue, then crystallize the residue from chloroform to give lO-hydroperoxy-17u-ethinyl-4-estrene-35, 175-diol l7-acetate.

To obtain the 3a-epimer thereof, evaporate the chloroform filtrate containing 10-hydroperoxy-l7ot-ethinyl-4- estrene-3,17-diol 17-acetate and crystallize the resultant precipitate withacetone-hexane to obtain 10-hydroperoxy- 17a-ethinyl-4-estrene-3u,l75-diol 17-acetate.

Example '5.-3-methoxy-17a-ethinyl-1,3,5 10) -estratrien- 175-o1 17-acetate and analogs thereof In a manner similar to that described in Example 1, treat 3-methoxy-l,3,5(10)-estratrien-17-one (estrone methyl ether) in dimethylformarnide under an atmosphere of nitrogen with sodium acetylide followed by acetic anhydride. Isolate the resultant product in a manner similar to that described in Example 1 to obtain 3-methoxy-l7uethinyl-1,3,5 (10)-estratrien-l75-ol 17 -acetate.

In a similar manner, treat each of the following with sodium acetylide in dirnethylformamide followed by acetic anhydride in the above described manner. 1-methyl-3-rnethoxy-l,3,5 (10)-estratrien-17-one, 2-methyl-3 -methoxy-1 ,3 ,5 10 -estratrien-17-one,

-1 ,2-dimethyl-3 -methoxy-1,3 ,5 (10)-estratrien-17-one, ,1,2-dirnethyl-3-methoxy-1,3,5 (10),6-estratetraen-17-one, .1-methyl-3-methoxy-L3 ,5 10) ,6-estratetraen-17-one, 2,3-di-methoxy-1,3,5 (10)-estratrien-17-one, 3-methoxy-l65-methyl-1,3 ,5 10)-estratrien-l7-one, 3-methoxy-1,3 ,5 l0) ,6-estratetraen-17-one,

as determined by S 3-methoxy-65-rnethyl-1,3 ,5 (10)-estratrien-l7-one, 3-methoxy-6-methyl-l,3 ,5 1O ,6-estratetraen-l7-one, 3-methoxy-1,3 ,5 10) ,9 l 1 -estratetraen-17-one, 3-methoxy-1,3,5 (l0) ,6,8-estrapentaen-17-one, and 3-methoxy-l,3 ,5 l0) ,7-estratetraen-l7-one.

Isolate the respective resultant products in a manner similar to that described in Example 1 to obtain l-methyl-3-methoxy-17a-ethinyl-1,3 ,5 10 -estratrier1- 17 5-01 17-acetate, 2-methyl-3 -methoxy-17 Ot-GthlIlYl-l ,3 ,5 l 0 -estratrien- 175-cl 17-acetate, 1,2-dimethyl-3 -methoxy- 17a-ethinyl-1 ,3 ,5 10 -estratrien- 17 5-01 17-acetate,

V 1,2-dirnethyl-3 -rnethoxy-l7a-ethinyl-1,3 ,5 l 0) ,6-estratetraen-175-ol l7-acetate,

1-methyl-3-methoxy-17a-ethinyl-1,3 ,5 (l0) ,G-estratetraen- 175-o1 17-acetate,

2,3-di-methoxy-17ot-ethinyl-1,3,5 10)-estratrien-17 5-01 17-acetate,

3-methoxy-l65-methyl-17ot-ethinyl-l,3 ,5 (10)-estratrien- 175-o1 17-acetate,

3 -methoxy-17ot-ethinyl-1,3 ,5 (10) ,6-estratetraen-175-ol l7-acetate,

3-methoxy-65-methyl-17u-ethinyl-1,3 ,5 10) -estr.atrien- 17 5-01 17-acetate,

3-methoxy-6-methyl-l7wethinyl-l,3,5(10),6-estratetraen- 175-o1 l7-acetate,

3 -methoxy-17-ethinyl-l,3 ,5 l0) ,9 l l -estratetraen- 175-o1 17-acetate,

3-methoxy-17a-ethinyl-1,3 ,5 l0) ,6,8-estrapentaen-175- ol l7-acetate, and

3-methoxy-17u-ethinyl-1,3,5(10),7-estratetraen-175-ol l7-acetate.

In the above procedure, if there is used an anhydride of other lower alkanoic acids such as propionic anhydride and-caproic anhydride, there is obtained the corresponding 17-alkanoate acids, i.e., the 17-propionate and 17- caproate, respectively, of each of the above listed compounds.

Example 6.-17ot-ethinyl-4-androsten-175-01-3 -one l7-acetate (A) 3-ethoxy 17o: ethinyl 3,5 androstadien-175- 01 17 acetate.-The requisite starting material, i.e., 3- ethoxy 3,5 androstadien l7 one is prepared according to known procedures via the action of ethyl orthoformate on 4 androstene 3.17 dione in dioxane in the presence of ethanol and a strong acid such as sulfuric acid or p-toluene sulfonic acid.

To a solution of 2 g. of 3 ethoxy 3,5 androstadienl7-one in 40 ml. of dimethylformamide under an atmosphere of nitrogen, add 0.69 g. of sodium acetylide. Stir at room temperature for 20 minutes, then add 1.1 ml. of acetic anhydride. Stir at room temperature for two minutes, then pour into 400 ml. of water containing 12 g. of sodium chloride. Filter the resulting precipitate comprising 3 ethoxy 17a ethinyl 3,5 androstadien- 175-01 17-acetate. Purify by crystallization from methanol containing a drop of pyridine.

In the above procedure, if propionic anhydride is substituted for acetic anhydride, there is obtained 3 ethoxyl7u-ethinyl-3,S-androstadien-175-o1 17-propionate.

(B) flat-ethinyl 4 androsten 175 ol 3 one 17- acetate (17a ethinyl-testosterone acetate).-Add 1 g. of 3-ethoxy 17a ethinyl 3,5 androstadien 175 ol 17-acetate to a solution comprising 190 ml. of methanol, 20 ml. of water, and 1.27 ml. of concentrated hydrochloric acid under an atmosphere of nitrogen. Allow this reaction mixture to stand under nitrogen at room temperature for three hours, then pour into Water. Filter the resulting precipitate comprising ethinyl 4 androsten ol 3 one l7-acetate. Purify by crystallization from acetone-hexane.

In a similar manner, treat 3 ethoxy 17a ethinyl- 01 17 propionate with an aqueous methanolic hydrochloric acid solution. Isolate the ethinyl-4-androsten-17 8-ol-3-one 17-propionate.

(C) In a manner similar to that described in Example treat each of the following with ethyl orthoformate in dioxane in the presence of ethanol and fonic acid: 19 nor 4 androstene 3,17 drone, 16 3- methyl 19 nor 4 androstene 3,17 dione, 4-androstene 3,11,17 trione, and 19 nor 4 androsten- 3,11,17 trione, and there is obtained their respective ethoxy enol ethers, namely, 3-ethoxy-19-nor-3,5-androstadien-17-one, 3-ethoxy-16B-methyl-l9-nor-3,5-androstadien-17-one, 3-ethoxy-3,S-androstadiene-11,17-dione, and 3-ethoxy-19-nor-3 ,5 -androstadiene-1 1, 1 7-dione.

In a manner similar to that described in the second paragraph of Example 6A, treat each of the foregomg ethoxy enol ethers with sodium acetylrde 1n dlrnethyl- 20 formamlde under nitrogen followed by acetic anhydrrde Isolate the respective resultant products in a manner slmrlar to that described to obtain 3-ethoxy-17a-ethinyl-19-nor-3,S-androstadien-Ufl-ol 17-acetate, 3-ethoxy-16fl-methyl-17a-ethinyl-19-nor-3,5-androstadien- 175-01 l7-acetate, 3-ethoxy-17a-ethinyl-3,5-androstadiene-17fi-ol-1l-one 17-acetate, and 3-ethoxy-17u-ethinyl-19-nor-3,5-androstadien-l7 3-01- ll-one 17-acetate.

In a manner similar to that described in Example 6B, treat each of the foregoing 3 ethoxy 17a ethinyl- 3,5 androstadienes with aqueous methanolic hydrochloric acid, and isolate the resultant product in a manner similar to that described to obtain, respectively, 17a-ethinyl-19-nor-4-androsten-17fi-ol-3-one 17-acetate (i.e., 17a-ethinyl-19-nor-testosterone l7-acetate), 16fl-methyl-17a-ethinyl-19-nor-4-androsten-17fi-ol-3-0ne 17-acetate, 17u-ethinyl-4-androsten-1719-01-3,l l-dione 17-acetate, and 1 7a-ethinyl-l9-nor-4-androsten-1 7,3-01-3, l l-dione 17- acetate.

Example 7.-l7a-ethinyl-17 3-acetoxy derivatives of hydroxylated androstanes and estranes Treat 40 g. of each of the following with dimethylformamide under an atmosphere of argon with sodlum acetyltde 1n the manner described in Example 1A fol- 5O lowed by treatment with acetic anhydrlde the quantity of acetic anhydride being approximately twice that used in Example 1 (i.e. around 39 ml. 5-androsten-3fl-ol-17-one, 4-androsten-3 3-ol-l7-one, 5-androsten-3a-ol-l7-one, 5-androstene-la,3 3diol-17-one,

1,3,5 1 0)-estratrien-3-ol-l7-one, l-methyl-1,3,5(10)-estratrien-3-ol-17-one,

1,2-dimethyl-1,3,5 10)-estratrien-3-0l-l 7-one, 1,2-dimethyl-1,3,5 10) ,6-estratetraen-3-ol-l7-one, 1-methyl-1,3,5 10),6-estratetraen-3-ol-17-one,

1,3,5 1 0) ,G-estratetraen-S-ol-l 7-one,

6;3-methyl-1,3,5 10)-estratrien-3-ol-l7-one,

6-methyl-1,3,5 10),6-estratetraen-3-ol-17-one, 1,3,5 l0) ,6,8-estrapentaen-3-ol-17-0ne,

1,3,5 10),7-estratetraen-3-ol-l7-One, and

6fi-methyl-1,3,5 10)-estratriene-3, 7a-diol-17-one.

Isolate the respective resultant products in a manner similar to that described in Example 1A to obtain 17a-ethinyl-5-androstene-35,17,8-diol diacetate, 17a-ethinyl-4-androstene-3B,17fi-diol diacetate, 17a-ethinyl-5-androstene-3a,17,8-di0l diacetate, l7a-ethinyl-5-androstene-1a,3fi,17fl-triol triacetate,

6fl-methyl-17a-ethinyl-1,3,5(10)-estratriene-3,7u,17 3-triol triacetate.

. namely the di- (or tri-) propionate, and the di- (or tri-) 'butyrate esters, respectively.

Example 8.17a-ethinyl-5-androstene-313,17,8-diol l7-acetate (A) 5-androsten-3fi-ol 17 one 3 tetrahydropyroanyl ether.-To a mixture of 1. g. of 5-andr0sten-3/3-0l-l7-one in 50 ml. of ether and l g. of 2,3 dihydropyran, add four drops of a prepared solution of p-toluene sulfonic acid (1 g.) in ml. of ether. Allow the reaction mixture to stand at room temperature for four days, then add an adsten-3fi-ol-17-one-3-tetrahydropyranyl ether, which is used without further purlfication in procedure 8B immediately following.

(B) l7oc-ethinyl-5-androstone-3,3,l7B-diol 3-tetrahydropyranyl ether 17-acetate.To a solution of 1 drost'en-3fi-ol-17-one 3-tetrahydropyranyl ether ru 30 ml.

Stir at room temperature five minutes, then pour, into a saturated aqueous solution of SOdlUIIl chloride. Collect by filtration the resulting precipitate comprising 17a-ethinyl- 5-androstene-3B,l7 3-diol 3-tetrahydropyranyl l7-acetate.

(C) 17u-ethinyl-5-androstene-3,8,17B-diol 17-acetate.- Dissolve 0.2 g. of 17a-ethinyl-5-androstene-3B,17fl-diol 3-tetrahydropyranyl ether 17-acetate in 40 ml. of ethanol,

cipitate comprising ethinyl-5-androstene-3 8,17 3-di0l 17-acetate. Purify by crystallization from acetate-hexane.

Alternatively, this example is prepared in the followin manner: To 3 g. of 17u-ethinyl-5-androstene-3,8,17fl-diol diacetate (prepared as described in Example 7), add 0.5 g. of carbonate in 100 ml. of methanol-water (9:1). Allow the reaction to stand at precipitate comprising 17a-ethinyl-5-androstene-3,B,l7fi-diol 17 acetate. Purify 'by crystallization from acetone-hexane.

(D) In a manner similar to that described in procedure 8A, treat each of -androsten-3a-0l-l7-ohe, and 4'-an'drosten-3fi-ol-l7-one with 2,3-dihydropyran in ether inthe presence of p-toluene sulfonic acid to obtain, respectively, 5-andr0sten-3u-0l-l7-0ne 3-tetrahydropyranyl ether and 4-androsten-3fi-ol-l7-one 3-tetrahydropyranyl ether. In the manner described in procedure 8B, treat each of the foregoing t'etrahydropyr'anyl ethers with sodium acetylide in dimethylformamide followed by acetic anhydride to ob.- tain, respectively, tetrahydropyranyl ether l7-acetate, and 17a-ethinyl-4-androstene-3 5,1718-diol 3-tetrahydropyranyl ether l7-acetate. Treat each of the foregoing l7a-ethinyl androstene 3-dihydropyranyl ether derivatives with aqueous ethanolic hydrochloric acid in the manner described in Example 80 to obtain, respectively, l7u-ethinyl-5-androstene-3a,l7fldiol l7-acetate, and 17a-ethinyl-4-androstene. 3B,17B'diol 17-acetate.

' 1. ml. of acetic anhydride.

Example 9.-l7a-Ethinyl-1,3,5(10)-estratriene-3,l7;8-diol 1 17-acetate (l7oc-ethiny1 estradiol 17acetate) (A) l,3,5(l0) estratrien-3fl-ol-l7-one 3 tetrahydropyranyl ether'.-In a manner similar to that described in Example 8A, treat 1,3,5 (l0)-estratrien-3-oI-l7-one ,1

with 2,3-dihydropyranyl in' ether in the presence of ptoluene sulfuric acid. Isolate the resultant product in a manner similar to that described to obtain 1,3,5 (10)- estratrien-3-ol-17-one 3-tetrahydropyranyl ether.

(B) l7u.-ethinyl-1,3,5(l0)-estratriene-3,l75-diol 3-tetrahydroether 17-acetate.--In a manner similar to that described in Example 8B, treat 1,3,5(l0)-estratrien-3-ol- 175-01 3-tetrahydropyranyl ether with sodium acetylide in dimethylformamide followed by treatment with acetic an hydride. Isolate the resultant product in the manner similar to that described to obtain l7a-ethinyl-1,3,5 (10)-estratriene-3,l7l9-diol 3-dihydropyranyl ether l7-acetate.

(C) l7a-ethinyl-1,3,5 (10)-estratriene-3,l75 diol l7- acetate.-In a manner similar to that described in Example 8C, treat 17a-ethinyl-l,3,5(10)-estratriene-3,17B- diol 3-tetrahydropyranyl ether 17-acetate with aqueous ethanolic hydrochloric acid. Isolate and purify theresultant product in the described manner to obtain 17dethiny1-1,3 ,5 l0) -estratriene-3, l7 fi-diol 17-aeetate.

Alternatively, the compound of this example is prepared as follows: Treat 17a-ethinyl-1,3,5(10)-estratriene- 3,17fi-diol diacetate (prepared as described in Example 7) with sodium carbonate in aqueous methanol in the manner described in the alternative procedure of Example 8C. Isolate and purify the resultant product in the described manner to obtain 17a-ethinyl-1,3,5(10)-estratriene-3,17fi-diol 17-acetate.

Example 10.-6fi-methyl-l 7a-ethinyl-l ,3,5 l0) -estratriene-3,7a, l7B-tri0l-17-acetate To 1 g. of 6fi-methyl-l7a-ethinyl-1,3,5(10)-estratriene- 3,7a,17;3-triol triacetate (prepared as described in Example 7), add 0.23 g. of sodium hydroxide dissolved in 60 ml. of methanol-water (9:1). Allow the reaction mixture to stand at room temperature for two hours, then add hydrochloric acid dropwise until the solution is about pH 5. Extract the reaction mixture with chloroform. Combine the chloroform extracts and evaporate to a residue comprising 6B-methyl-17a-ethinyl-l,3,5(l0) estratriene- Example 11.--17a-ethinyl-androstane-l16,17fl-diol l7- acetate .To a solution of 2.9 g. of androstan-11fi-ol-l7-one in 70 ml. of dimethylformamide under an argon, add 0.48 g. of sodium acetylide. Stir at room temperature for 15 minutes, then add'rapidly 1.02 gpof acetic anhydride. Stir at room temperature for one minute, then pour into 500 ml. of water saturated with sodium chloride. Continue. stirring under an atmosphere of argon for two hours, then collect by filtration the resultant atmosphere of v 12 precipitate comprising"'l7og-ethinyhandrostane 1118,173- diol l7=acetatexi I Example l2;:3-methoxy 17a-propynyl-2,5 (10) -estra- To 'a solution of 0;4*g.' of'3-m'ethoxy-2,5 (10)estradienl7"-one in 8.5 m1: ofdimethylformamide under an atmosphere-of nitrogen, add (){136 g.--o'f-a sodium salt of methyl acetylene (i.e. the sodium salt of'propyne) dispersed in xylene (prepared according to'known' procedures by placing propyne into a solution of liquid ammonia and sodium, and then displacingthe ammonia with xylene). Stir atroomternperatur e. for 20 minutes, then add,0.21 Stir the reaction mixture for five minutes at room temperature, then pour-the reaction mixture into an aqueous saturated sodiumchloride solution. Extract the mixture with methylene 'fchloride and evaporate the combined methylene chlo 'deext racts to a residue comprising Za-iiietho'xy-1 7o propy yl-2,5 (l0) festr'adierh -01 l7-acet'ate. Purifyby crystallization'from aqueous ethanol containing a drop ofpyridine. v f

In the above procedure, if in place of acetic anhydride there is used the anhydride of'other lower alkanoic acids, such as propionic and n-butyric 'anhydride,-there is obtained the corresponding lower alkanoic acidester, i.e. 3'- methoxy-l7a-propynyl-2,5 l0) -estradien-l7 8-01 17-propionate, and. 3-methoxy-l7a-propynyl-2,5(10) estradien- 1773-01 l7 butyrate, respectively.

I claim: v

1. A process for preparing a l7a-alkynyl-l7f3-alkanoyloxy. steroid of the androstane and estraneseries which comprises treating a l7-keto steroid offthe .androstane and estrane series with an alkali metal acetylideyadding in situ to the .,l7a-alkynyll7fi-hydroxy metal salt intermediate thereby formedan acylating agentselected from the group consisting of a lower alkanoyl anhydride and a lower alkanoyl halide; and'treating said metal salt intermediate with said acylating agent for less than an hour at temperatures up to 50 C.

2. The process of claim 1 when carried out in an N,N- disubstituted lower alkanoic acid amide.

3. The process of claim 1 when carried out in tetrahydrofuran.

4. The process of claim lwherein said-alkali metal acetylide is sodium acetylide.- V.

5. The process of claim 1 wherein said alkali metal acetylide is sodium acetylide and w herein said acylating agentis a lower alkanoic anhydride. I

6. The process of claim 1 wherein said alkali metal acetylide'is sodium acetylide and wherein said acylating agent is a lower alkanoyl halide. p

7. The process of claim 1 when carried out in dimethylformamide and wherein said alkalimetal acetylide is so dium acetylide and wherein said acylating agent is a lower alkanoic anhydride.

8. The process accordingto claim 7 wherein said lower alkanoic anhydride is acetic anhydride.

9. A process for preparing 3-alkoxy-17a-alkynyl-17,8- alkanoyloxy- 2,5(l0)-estradiene;which comprises treating 3-alkoxy-2,5 ('10)-estradien-17-one with an alkali metal acetylide; and: adding in situ .tothe l7a-alkynyl-l7B-hydroxy metal salt intermediate thereby formed an acylating agent selectedfrom the group consisting. of a lower alkanoyl anhydride. and a lower alkanoyl halide.

10. A process according to claim 9 when carried out in dimethylforrnamide and wherein said 3-alkoxy-2,5 (l0)- estradien-17-one is 3-methoxy-2,5(l0)-estradien-l7-one, said alkali metal acetylide is sodium acetylide, said acylating agent is acetic anhydride, and wherein said 3-alkoxyl7a-alkynyl-l7fi-alkanoyloxy-2,5 loj-estradiene prepared is 3 methoxy-17a-ethinyl-2,5(10)-estradien-l7p-o1 17- acetate', v v

said -proces for preparing 3-methoxy-l7a-ethinyl-2,5

(l0)-estradien--l7fl-ol 17-acetate comprising treating 3 methoxy 2,5(10)-estradien-l7-one with sodium acetylide in dimethylformamide; and adding acetic 14 3,076,829 2/1963 Reimann et a1 anhydride in situ to the thereby formed 260397.45 17a-ethinyl- 3,260,733 7/1966 Foell et a1. 260397.3 l7fi-hydroxy sodium salt intermediate. OTHER REFERENCES References Cited 5 Lowenthal, Letrohedion 6, pp. 269-303 (1959) (p. 300 UNITED STATES PATENTS relied 2,970,157 1/1961 Cutler et a1 3,072,646 1/1963 Fried et a1. 3,072,686 I/ 1963 Wettstein 260397.45 LEWIS GOTTS, Primary Examiner. 260-23955 et aL 260 397 4 E. G. LOVE, Assistant Examiner. 

